Synthetic methodology for the reductive alkylation at the C-3 position of indoles

ABSTRACT

A process for the reductive alkylation at the C-3 position of an indole compound in which the indole is treated with an aldehyde in the presence of a Lewis acid and a silicon hydride reducing agent. The process is useful for alkylating the C-3 position of indoles that contain acid-sensitive substituents at the N-1 position.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit under 35 U.S.C. § 119(e) toProvisional Application Ser. No. 60/529,797, Filed: Dec. 16, 2003, ofwhich application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to synthetic methodology for the reductivealkylation at the C-3 position of indoles.

BACKGROUND

C-3 alkylation of indoles in general is a facile process, as shown inComprehensive Organic Chemistry, 1979, V. 4, Chapter 17, “Indoles andRelated Systems”. This alkylation can occur under basic or acidicreaction conditions. The effect of different metal cations, baseconcentration, and catalysts for the phase transfer alkylation ofindoles under basic conditions has been studied. Alkylation of indolesunder acidic reaction conditions can often proceed with catalyticamounts of acid catalysts. An examination of the literature reveals alarge number of acid catalysts that have been used for the C-3alkylation of indoles.

It is convenient to achieve both alkylation and reductiontransformations simultaneously when indoles with C-3 saturatedsubstituents are desired. Triethylsilane is a convenient reducing agentunder acidic reaction conditions, and trifluoroacetic acid andtriethylsilane have been used as a reagent combination to accomplishsimultaneous alkylation and reduction at the C-3 position of indoles;Steele, et al. Tet Lett 1993, p1529. Unfortunately, trifluoroacetic acidis incompatible with some acid sensitive functional groups, and, infact, trifluoroacetic acid is well known as a reagent for the cleavageof benzhydryl protecting groups; Greene and Wuts, “Protective Groups inOrganic Synthesis” 3^(rd) ed., John Wiley & Sons, 1999.

SUMMARY

The present invention comprises a process for the reductive alkylationat the C-3 position of an indole compound, the process comprisingtreating the indole with an aldehyde in the presence of a Lewis acid anda silicon hydride reducing agent. The process is particularly useful foralkylating the C-3 position of indoles that contain acid-sensitivesubstituents at the N-1 position.

In particular embodiments, the indole has the formula

wherein the variables R, R¹, R³, R⁴, R⁵, R⁶, X¹, n₁, and n₂ are definedas described herein. Acid-sensitive groups that may be present at theN-1 position of the indole include, for example, those having theformula

wherein X³ and X⁴ are defined as described herein. Particular examplesof acid-sensitive groups include, for example, benzhydryl,2,4-dimethoxybenzyl, 2-hydroxybenzyl, 5-dibenzosuberyl, triphenylmethyl,and the like.

DETAILED DESCRIPTION

Methods of the present invention for the reductive alkylation at the C-3position of an indole compound comprise treating the indole with analdehyde in the presence of a Lewis acid and a silicon hydride reducingagent. The methods are particularly useful for alkylating the C-3position of indoles that contain acid-sensitive substituents at the N-1position.

Suitable silicon hydride reducing agents include, for example,phenylmethylsilane, diphenylsilane, triphenylsilane, and tri(C₁-C₄alkyl)silanes, such as trimethylsilane and triethylsilane. SuitableLewis acids include salts comprising a cation selected from boron,aluminum, antimony and rare earth metals such as scandium or lanthanum,particularly in combination with a halogen or triflate anion. Othersuitable Lewis acids include pentafluorophenylmetallic acids in whichthe metal is boron, aluminum, antimony or a rare earth metal.Preferably, the Lewis acid comprises a fluoride, chloride, or triflatesalt of boron, aluminum, antimony or a rare earth metal, and/orcomprises pentafluorophenylboronic acid. Examples of suitable Lewisacids include, for example, boron trifluoride (BF₃), borontris(trifluoromethanesulfonate), aluminum trichloride (AlCl₃), aluminumtrifluoride (AlF₃), pentafluorophenylboronic acid, and lanthanumtrifluoromethanesulfonate.

In some embodiments, after the reaction has begun (i.e. aftercombination of the indole, aldehyde, silicon hydride reducing agent, andthe Lewis acid) a suitable organic acid, e.g., trifluoroacetic acid,CCl_(x)H_(3-X)CO₂H (where X is 0-3), or an aryl sulfonic acid (e.g.,p-toluenesulfonic acid or benzenesulfonic acid) may be added to thereaction mixture to increase the rate of conversion of the reactants tothe final product. The organic acid may be added some time after thereaction has begun, for example, approximately 30-60 minutes after thereaction has begun. The reaction is preferably conducted at atemperature in the range of approximately −30° C. to +25° C.

Embodiments of the invention include those where the indole has theformula

wherein

-   -   R is selected from the group consisting of —(CH₂)_(n3)-A,        —(CH₂)_(n3)—S-A, and —(CH₂)_(n3)—O-A, wherein A is selected from        the group consisting of:

-   -   wherein        -   E is selected from the group consisting of H, C₁-C₆ alkyl,            C₁-C₆ alkoxy, —CF₃, and —(CH₂)_(n4)—CF₃; and        -   D and G independently are selected from the group consisting            of phenyl, pyridinyl, pyrimidinyl, furyl, thienyl and            pyrrolyl, each optionally substituted by from 1 to 3,            preferably 1 to 2, substituents selected independently from            H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆            alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),            —NH—C(O)—(C₁-C₆ alkyl), —NO₂, and a 5- or 6-membered            heterocyclic or heteroaromatic ring containing 1 or 2            heteroatoms selected from O, N or S;    -   X¹ is selected from the group consisting of a chemical bond,        —S—, —O—, —S(O)—, —S(O)₂—, —NH—, —NHC(O)—, —C═C—,

-   -   R¹ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆        fluorinated alkyl, C₃-C₆ cycloalkyl, tetrahydropyranyl,        camphoryl, adamantyl, CN, —N(C₁-C₆ alkyl)₂, phenyl, pyridinyl,        pyrimidinyl, furyl, thienyl, napthyl, morpholinyl, triazolyl,        pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl,        thiazolidinyl, thiomorpholinyl, tetrazole, indole, benzoxazole,        benzofuran, imidazolidine-2-thione, 7,7,        dimethyl-bicyclo[2.2.1]heptan-2-one, benzo[1,2,5]oxadiazole,        2-oxa-5-aza-bicyclo[2.2.1]heptane, piperazin-2-one and pyrrolyl,        each optionally substituted with 1 to 3 substituents        independently selected from the group consisting of H, halogen,        —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, —(C₁-C₆ alkyl)-R⁷,        C₁-C₆ alkoxy, —(C₁-C₆ alkoxy)-R⁷, —C(O)—(C₁-C₆ alkyl), —NH₂,        —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆        alkyl)-N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)-NH(C₁-C₆ alkyl),        —NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH₂,        —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —COOH, —C(O)O—(C₁-C₆        alkyl), —(C₁-C₆ alkyl)-COOH, 1-chloro-2-methyl-propyl, —C₁-C₆        thioalkyl, —(C₁-C₆ alkyl)C(O)CH₃, —(C₁-C₆ alkyl)OCH₃, C(O)NH₂,        phenyl, benzyl, benzyloxy, morpholino, pyrrolidino, piperidine,        piperizine, furan, thiophene, imidazole, tetrazole, pyrazine,        pyrazolone, pyrazole, imidazole, oxazole, isoxazole, thiazole,        2-methyl-thiazole,

-   -   R³ is selected from the group consisting of H, halogen, —CN,        —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),        —NH—C(O)—(C₁-C₆ alkyl), and —NO₂;    -   R⁴ is selected from the group consisting of H, halogen, —CN,        —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),        —NH—C(O)—(C₁-C₆ alkyl), —NO₂, —NH—C(O)—NH(C₁-C₆ alkyl)₂,        —NH—C(O)—NH(C₁-C₆ alkyl), —NH—C(O)—O—(C₁-C₆ alkyl), —SO₂—(C₁-C₆        alkyl), —S—(C₃-C₆ cycloalkyl), —S—CH₂—(C₃-C₆ cycloalkyl),        —SO₂—(C₃-C₆ cycloalkyl), —SO₂—CH₂—(C₃-C₆ cycloalkyl), C₃-C₆        cycloalkyl, —CH₂—(C₃-C₆ cycloalkyl), —O—(C₃-C₆ cycloalkyl),        —O—CH₂—(C₃-C₆ cycloalkyl), phenyl, benzyl, benzyloxy,        morpholino, pyrrolidino, piperidine, piperizine furan,        thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole,        imidazole, oxazole and isoxazole, the rings of each of these R₄        groups each being optionally substituted by from 1 to 3        substituents selected from the group consisting of H, halogen,        —CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆        alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), —NO₂,        —SO₂(C₁-C₆ alkyl), —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, and        —OCF₃;    -   R⁵ and R⁶ independently are selected from the group consisting        of H and C₁-C₆ alkyl;    -   alternatively, R⁵ and R⁶ together with the atom to which they        are bonded form C₃-C₆ cycloalkyl;    -   R⁷ is selected from the group consisting of phenyl, benzyl,        benzyloxy, morpholino, pyrrolidino, piperidine, piperizine,        furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone,        pyrazole, imidazole, oxazole, isoxazole, thiazole,        2-methylthiazole, each being optionally substituted by from 1 to        3 substituents selected from the group consisting of H, halogen,        —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —C(O)—(C₁-C₆        alkyl), —C(O)O—(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆        alkyl), —NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl),        —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, and OCF₃;    -   n₁ is an integer selected from 1, 2, or 3;    -   n₂ is an integer selected from 0, 1, 2, 3, or 4;    -   n₃ is an integer selected from 0, 1, 2, or 3; and    -   n₄ is an integer selected from 1, 2, or 3.

It will be understood that the C₁-C₆ fluorinated alkyl groups in thedefinition of R¹ may be any alkyl group of 1 to 6 carbon atoms with anyamount of fluorine substitution including, but not limited to, —CF₃,alkyl chains of 1 to 6 carbon atoms terminated by a trifluoromethylgroup, —CF₂CF₃, etc.

In the definition of X₁, the alkenyl bridging group —C═C— is understoodto indicate either the cis or trans orientation of the indicatedcompound(s).

Acid-sensitive groups that may be present at the N-1 position of theindole include, for example, those having the formula

wherein X³ and X⁴ independently are selected form the group consistingof H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy,—NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and—NO₂. A particular example of an acid-sensitive group is benzhydryl(i.e., wherein X³ is H and X⁴ is H).

Other examples of acid-sensitive groups include, for example,2,4-dimethoxybenzyl, 2-hydroxybenzyl, 5-dibenzosuberyl, triphenylmethyl,and the like, each optionally substituted with 1 to 3, preferably 1 to2, substituents selected independently from H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂,—NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂.

In particular embodiments, the indole has the structure

-   -   wherein    -   X³ and X⁴ independently are selected from the group consisting        of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆        alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),        —NH—C(O)—(C₁-C₆ alkyl), and —NO₂; and    -   X⁵, X⁶, X⁷, and X⁸ independently are selected from the group        consisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆        alkyl, —(C₁-C₆ alkyl)-R⁷, C₁-C₆ alkoxy, —(C₁-C₆ alkoxy)-R⁷,        —C(O)—(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),        —(C₁-C₆ alkyl)-NH₂, —(C₁-C₆ alkyl)-N(C₁-C₆ alkyl)₂, —(C₁-C₆        alkyl)-NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆        alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂,        —COOH, —C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-COOH,        1-chloro-2-methyl-propyl, —C₁-C₆ thioalkyl, —(C₁-C₆        alkyl)C(O)CH₃, —(C₁-C₆ alkyl)OCH₃, C(O)NH₂, phenyl, benzyl,        benzyloxy, morpholino, pyrrolidino, piperidine, piperizine,        furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone,        pyrazole, imidazole, oxazole, isoxazole, thiazole,        2-methyl-thiazole,

the rings of each of these X⁵, X⁶, X⁷, and X⁸ groups each beingoptionally substituted by from 1 to 3 substituents selected from thegroup consisting of halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆alkoxy, —C(O)—(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, and OCF₃.

Examples of these embodiments include compounds wherein X³ is H, X⁴ isH, X⁵ is —CF₃, X⁶ is H, X⁷ is H, and X⁸ is H. Other examples includethose wherein X³ is H, X⁴ is H, X⁵ is —CH₃, X⁶ is H, X⁷ is H, and X⁸ is—CH₃. In still other examples, X³ is H, X⁴ is H, X⁵ is H, X⁶ is Cl, X⁷is Cl, and X⁸ is H.

In some embodiments, the aldehyde has the formula

-   -   wherein    -   X² is selected from the group consisting of —O—, —CH₂—, —S—,        —SO—, —SO₂—, —NH—, —C(O)—, —NHSO₂—,

-   -   R² is a ring moiety selected from the group consisting of        phenyl, pyridinyl, pyrimidinyl, furyl, thienyl and pyrrolyl, the        ring moiety being substituted by a group of the formula        —(CH₂)_(n6)—CO₂R⁸ or a pharmaceutically acceptable bioisostere,        and optionally further substituted by 1 or 2 substituents        independently selected from the group consisting of halogen,        —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),        —NH—C(O)—(C₁-C₆ alkyl), and —NO₂;    -   R⁸ is selected from the group consisting of H and C₁-C₆ alkyl;    -   n₅ is an integer selected from 0, 1, 2, or 3; and    -   n₆ is an integer selected from 0, 1, or 2.

Pharmaceutically acceptable carboxylic acid bioisosteres useful in thecompounds of this invention include, but are not limited to, thefollowing, which are bonded to R²:

wherein R^(a) is selected from —CF₃, —CH₃, phenyl, or benzyl, with thephenyl or benzyl groups being optionally substituted by from 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —CF₃,halogen, —OH, or —COOH; R^(b) is selected from —CF₃, —CH₃, —NH₂, phenyl,or benzyl, with the phenyl or benzyl groups being optionally substitutedby from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —CF₃, halogen, —OH, or —COOH; and R^(c) is selected from —CF₃or C₁-C₆ alkyl.

In particular embodiments of the invention, the aldehyde has the formula

-   -   wherein R⁸ comprises a C₁-C₆ alkyl group. After the reaction        between the indole and the aldehyde has taken place, the R⁸        group may optionally be removed to form a carboxylic acid.

According to an embodiment of the invention, the acid sensitive groupbonded to the N-1 nitrogen comprises benzhydryl, the Lewis acidcomprises BF₃, and the silicon hydride reducing agent comprisestriethylsilane. The reaction may take place at approximately −20° C. Inaddition, trifluoroacetic acid may be added approximately 30-60 minutesafter the reaction begins.

An illustrative embodiment of the present invention is shown in Scheme1, in which an indole is alkylated at the C-3 position in the firstreaction step and in a second reaction step the ester group of the C-3substituent is cleaved to produce a carboxylic acid. The acid sensitivegroup in this reaction scheme is an N-benzhydryl group. In this example,boron trifluoride is the Lewis acid and is added in the form of acomplex with diethyl ether (i.e., borontrifluoride diethyl etherate,BF₃OEt₂), and triethylsilane (Et₃SiH) is the silicon hydride reducingagent. Trifluoroacetic acid (TFA) is added 30-60 minutes after thealdehyde, indole, BF₃OEt₂ and Et₃SiH are combined and, therefore, afterthe reaction has begun.

Attempts to react indole 1 with aldehydes such as 3 usingtrifluoroacetic acid and triethylsilane in the absence of a Lewis acidsuch as boron trifluoride, a Lanthanide triflate, orpentafluorophenylboronic acid result in extensive loss of the benzhydrylgroup at the N-1 position, which leads to almost complete removal of thegroup from the molecule or rearrangement to other areas of the indolestructure. The combined use of a Lewis acid such as boron trifluoride, aLanthanide triflate, or pentafluorophenylboronic acid and triethylsilanehas not previously been reported as a reagent combination to alkylatethe C-3 position of indoles.

Lewis acids such as boron trifluoride, Lanthanide triflates, orpentafluorophenylboronic acid are effective replacements fortrifluoroacetic acid in reductive alkylation at the C-3 position ofindoles containing acid-sensitive functional groups. For example,referring again to Scheme 1, treating indole 1 or 2 with aldehyde 3 inthe presence of boron trifluoride and triethylsilane results in greaterthan 95% conversion with 80-85% selectivity to compounds 4 or 5,respectively, under favorable reaction conditions. These intermediatescan conveniently be carried forward in a further reaction to hydrolyzethe ester functional group to give compounds of formula 6 or 7,respectively.

In addition, the combination of a Lewis acid such as boron trifluoridewith an organic acid such as trifluoroacetic acid can exert asynergistic effect on the rate of the reductive alkylation reaction.Referring to Scheme 2, a reaction performed in the absence oftriethylsilane gives complete conversion of 9 to bis-alkylated dimer 10.When the reaction is performed with boron trifluoride and triethylsilanebut without trifluoroacetic acid, the conversion to 10 is rapid,followed by a slow conversion of 10 to the desired product 11.

Preferred reaction conditions are an initial addition of borontrifluoride to a mixture of indole 8, aldehyde, and triethylsilane inmethylene chloride as solvent, followed by addition of trifluoroaceticacid after 30-60 minutes. Under these conditions the alkylated dimer 10is more rapidly converted to the desired product while minimizing theformation of rearranged byproducts. Preferably, the reaction of theindole and the aldehyde takes place at a temperature in the approximaterange of form −30° C. to +25° C., most preferably at about −20° C.

Without intending to limit the present invention to any particularmechanism, this behavior can be mechanistically explained by theactivation of the aldehyde carbonyl functional group towards alkylationof the C-3 position of the indole to form dimer 10, presumably through acationic intermediate or transition state such as 12. Trifluoroaceticacid is more effective than boron trifluoride at activating 10 todissociation to form 12 and starting material, with the net effect ofincreasing the concentration of 12, and thus the rate of its reduction,in the reaction mixture.

Particular compounds synthesized according to the invention inhibitcPLA2 activity that is required for supplying arachidonic acid substrateto cyclooxygenase-1 or -2 and 5-lipoxygenase, which in turn initiate theproduction of prostaglandins and leukotrienes respectively. In addition,cPLA2 activity is essential for producing the lyso-phospholipid that isthe precursor to PAF. Thus these compounds may be useful in thetreatment and prevention of disease states in which leukotrienes,prostaglandins or PAF are involved. Moreover, in diseases where morethan one of these agents plays a role, a cPLA2 inhibitor would beexpected to be more efficacious than leukotriene, prostaglandin or PAFreceptor antagonists and also more effective than cyclooxygenase or5-lipoxygenase inhibitors.

These compounds may be especially useful in the treatment ofinflammatory conditions, such as arthritic and/or rheumatic disorders,including but not limited to rheumatoid arthritis,spondylo-arthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. The compounds of this inventionmay be useful in the treatment of post-operative inflammation includingthat following ophthalmic surgery such as cataract surgery or refractivesurgery. In addition, the compounds of the invention may be useful inthe treatment of asthma.

The following examples are presented to illustrate certain embodimentsof the present invention, but should not be construed as limiting thescope of this invention.

EXAMPLE 14-(3-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicAcid

N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichlorophenyl)-methanesulfonamide(20.0 g, 34.25 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (10.5 g,50.97 mmol), triethylsilane (12.0 g, 103.5 mmol), magnesium sulfate(0.30 g), and dichloromethane (100 mL) were combined, stirred, andcooled to −20° C. A solution of boron trifluoride diethyl etherate (3.26g, 22.96 mmol) in dichloromethane (10 mL) was added to the reactionmixture over 2 min. After 40 min, trifluoroacetic acid (1.95 g, 17.11)was added to the reaction mixture. After three hours, the reactionmixture was filtered cold through a celite pad into aqueous sodiumbicarbonate (9 g/100 mL). The organic layer was concentrated to 60 g,then methanol (100 mL) was added. The solution was concentrated to 82 g.Methanol (40 mL) and aqueous sodium hydroxide (8.2 g of a 50% solution,102.5 mmol) were added to the mixture. The mixture was stirred andwarmed to 65° C. for 6 h. After cooling the reaction mixture to roomtemperature, acetic acid (6.2 g, 102.5 mmol) was added and the solvent(40 g) was removed. Toluene (200 mL) and water (50 mL) were added to themixture. The organic layer was separated and washed with water (10 mL),then concentrated to 78 g. The solid product was collected by filtrationafter standing overnight, then recrystallized from 10 parts of tolueneto give 13.2 g (52%) of the title compound. ¹H NMR (DMSO_(-d6)): δ12.80(br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d, 1H,J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd,1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m, 2H),2.96 (m, 2H), 2.76 (m, 4H), 1.90(m, 2H). MS: 744 MW, 99.8%.

EXAMPLE 24-(3-{1-Benzhydryl-5-chloro-2-[2-(2,6-dimethyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic Acid

N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethyl-phenyl)-methanesulfonamide(300 g, 552 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (250 g,1.21 mol), triethylsilane (192 g, 1.66 mol), and dichloromethane (2.9 L)were combined, stirred, and cooled to −20° C. A solution of borontrifluoride etherate (55.0 g, 322 mmol) in dichloromethane (10 mL) wasadded to the reaction mixture over 9 min. After 35 min, trifluoroaceticacid (63 g, 553 mmol) was added to the reaction mixture. After 40 min,the reaction mixture was filtered cold through a celite pad into aqueoussodium bicarbonate (138 g/1.5 L). The organic layer was concentrated to1.2 L g, then ethanol (1.5 L) was added. The solution was concentratedto 1.2 L. THF (450 mL) and a solution of aqueous sodium hydroxide (221g, 2.76 mol) were added. The reaction mixture was then warmed to refluxfor 30 min. The mixture was cooled to 50° C. Toluene (1.5 L), water (300mL) and acetic acid (166 g, 2.76 mol) were added. The organic andaqueous phases were separated and the organic phase was concentrated to1.2 L. Toluene (600 mL) was added and the mixture was concentrated to1.2 L. The mixture was cooled to room temperature and stirred for 16 h.The solid was collected by filtration, washed with cold toluene (3×300mL), and dried to give 317 g (81%) of the title compound.

Many variations of the present invention not illustrated herein willoccur to those skilled in the art. The present invention is not limitedto the embodiments illustrated and described herein, but encompasses allthe subject matter within the scope of the appended claims.

1. A method for the reductive alkylation at the C-3 position of anindole, said method comprising treating the indole with an aldehyde inthe presence of a silicon hydride reducing agent selected from the groupconsisting of tri(C₁-C₄ alkyl)silane, triphenylsilane, diphenylsilaneand phenylmethylsilane, and a Lewis acid selected from the groupconsisting of salts of boron, aluminium, antimony or a rare earth metaland a halogen or triflate anion, and pentafluorophenylmetallic acids inwhich the metal is boron, aluminium, antimony or a rare earth metal; andsubsequently adding an organic acid to the reaction mixture after thereaction has begun, wherein the organic acid is selected from the groupconsisting of trifluoroacetic acid, CCl_(X)H_(3-X)CO₂H where X is 0-3,p-toluenesulfonic acid, and benzenesulfonic acid.
 2. The method of claim1 wherein the organic acid is added approximately 30-60 minutes afterthe reaction has begun.
 3. The method according to claim 1 or 2, whereinthe indole comprises an acid-sensitive substituent bonded to the N-1nitrogen.
 4. The method claim 3 wherein the acid-sensitive substituentis selected from the group consisting of benzhydryl,2,4-dimethoxybenzyl, 2-hydroxybenzyl, 5-dibenzosuberyl, andtriphenylmethyl, and is optionally substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, —CN, —CHO,—CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂,—NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂.
 5. The methodaccording to claim 1 wherein the Lewis acid is selected from the groupconsisting of a flouride, chloride, or triflate salt of boron,aluminium, antimony or a rare earth metal, and pentafluorophenylboronicacid.
 6. The method of claim 5 wherein the Lewis acid is selected fromthe group consisting of BF₃, boron tris(trifluoromethanesulfonate), andpentafluorophenylboronic acid.
 7. The method according to claim 1wherein the silicon hydride reducing agent is triethylsilane.
 8. Themethod according to claim 1 wherein the reaction takes place at atemperature in the range of from about −30° C. to about +25° C.
 9. Amethod for the reductive alkylation at the C-3 position of an indole,wherein the indole comprises a compound of the formula

wherein R is selected from the group consisting of —(CH₂)_(n3)-A,—(CH₂)_(n3)—S-A, and —(CH₂)_(n3)—O-A, wherein A is selected from thegroup consisting of:

wherein E is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkoxy, —CF₃, and —(CH₂)_(n4)—CF₃; and D and G independently areselected from the group consisting of phenyl, pyridinyl, pyrimidinyl,furyl, thienyl and pyrrolyl, each optionally substituted by from 1 to 3substituents selected independently from halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), NO₂, and a 5- or 6-membered heterocyclic orheteroaromatic ring containing 1 or 2 heteroatoms selected from O, N andS; X¹ is selected from the group consisting of a chemical bond, —S—,—O—, —S(O)—, —S(O)₂—, —NH—, —NHC(O)—, —C═C—,

R¹ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆fluorinated alkyl, C₃-C₆ cycloalkyl, tetrahydropyranyl, camphoryl,adamantyl, —CN, —N(C₁-C₆ alkyl)₂, phenyl, pyridinyl, pyrimidinyl, furyl,thienyl, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl,pyrrolidinyl, imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl,tetrazolyl, indolyl, benzoxazolyl, benzofuryl, imidazolidinyl-2-thione,7,7-dimethyl-bicyclo[2.2.1]heptyl-2-one, benzo[1.2.5]oxadiazolyl,2-oxa-5-aza-bicyclo[2.2.1]heptyl, piperazinyl-2-one and pyrrolyl, eachoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆alkyl, —(C₁-C₆ alkyl)-R⁷, C₁-C₆ alkoxy, —(C₁-C₆ alkoxy)-R⁷, —C(O)—(C₁-C₆alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —(C₁-C₆ alkyl)—NH₂,—(C₁-C_(-C) ₆ alkyl)-N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)-NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆alkyl), —SO₂N(C₁-C_(6 alkyl)) ₂, —COOH, —C(O)O—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-COOH, 1-chloro-2-methyl-propyl, —C₁-C₆ thioalkyl, —(C₁-C₆alkyl)C(O)CH₃, —(C₁-C₆ alkyl)OCH₃, C(O)NH₂, phenyl, benzyl, benzyloxy,morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl,imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 2-methyl-thiazolyl,

R³ is selected from the group consisting of H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂; R⁴ isselected from the group consisting of H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆alkyl)₂, —NH(C₁-C₆ alkyl), —NHC(O)—(C₁-C₆ alkyl), —NO₂,—NH—C(O)—NH(C₁-C₆ alkyl)₂, —NH—C(O)—NH(C₁-C₆ alkyl), —NH—C(O)—O—(C₁-C₆alkyl), —SO₂—(C₁-C₆ alkyl), —S—(C₃-C₆ cycloalkyl), —S—CH₂—(C₃-C₆cycloalkyl), —SO₂—(C₃-C₆ cycloalkyl), —SO₂—CH₂—(C₃-C₆ cycloalkyl), C₃-C₆cycloalkyl, —CH₂—(C₃-C₆ cycloalkyl), —O—(C₃-C₆ cycloalkyl),—O—CH₂—(C₃-C₆ cycloalkyl), phenyl, benzyl, benzyloxy, morpholinyl,pyrrolidinyl, piperidinyl, piperazinyl furyl, thienyl, imidazolyl,tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl and isoxazolyl,the rings of each of these R₄ groups each being optionally substitutedby from 1 to 3 substituents selected from the group consisting ofhalogen, —CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆alkyl), —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, and —OCF₃; R⁵ and R⁶independently are selected from the group consisting of H and C₁-C₆alkyl; or R⁵ and R⁶ together with the atom to which they are bonded formC₃-C₆ cycloalkyl; R⁷ is selected from the group consisting of phenyl,benzyl, benzyloxy, morphlinyl, pyrrolidinyl, piperidinyl, piperazinyl,furyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,2-methyl-thiazolyl, each being optionally substituted by from 1 to 3substituents selected from the group consisting of halogen, —CN, —CHO,—CF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —C(O)—(C₁-C₆ alkyl), —C(O)O—(C₁-C₆alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)₂, and —OCF₃; n₁ is an integer selected from 1, 2, or 3; n₂ is aninteger selected from 0, 1, 2, 3, or 4; n₃ is an integer selected from0, 1, 2, or 3; and n₄ is an integer selected from 1, 2, or 3; the methodcomprising treating the indole with an aldehyde in the presence of asilicon hydride reducing agent selected from the group consisting oftri(C₁-C₄ alkyl)silane, triphenylsilane, diphenylsilane andphenylmethylsilane, and a Lewis acid selected from the group consistingof salts of boron, aluminium, antimony or a rare earth metal and ahalogen or triflate anion, and pentafluorophenylmetallic acids in whichthe metal is boron, aluminum, antimony or a rare earth metal.
 10. Themethod of claim 9, wherein R has the formula

wherein X³ and X⁴ independently are selected form the group consistingof H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,—NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and—NO₂.
 11. The method of claim 10, wherein X³ is H; and X⁴ is H.
 12. Themethod of claim 9, wherein the indole comprises a compound of theformula

wherein X³ and X⁴ independently are selected from the group consistingof H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,—NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and—NO₂; and X⁵, X⁶, X⁷, and X⁸ independently are selected from the groupconsisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl,—(C₁-C₆ alkyl)-R⁷, C₁-C₆ alkoxy, —(C₁-C₆ alkoxy)-R⁷, —C(O)—(C₁-C₆alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-NH₂,—(C₁-C₆ alkyl)-N(C₁-C₆ alkyl)₂, —(C₁-C₆ alkyl)-NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆alkyl), —SO₂N(C₁-C₆ alkyl)₂, —COOH, —C(O)O—(C₁-C₆ alkyl), —(C₁-C₆alkyl)-COOH, 1-chloro-2-methyl-propyl, C₁-C₆ thioalkyl, —(C₁-C₆alkyl)C(O)CH₃, —(C₁-C₆ alkyl)OCH₃, —C(O)NH₂, phenyl, benzyl, benzyloxy,morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl,imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 2-methyl-thiazolyl,

 the rings of each of these X⁵, X⁶, X⁷, and X⁸ groups each beingoptionally substituted by from 1 to 3 substituents selected from thegroup consisting of halogen, —CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl, C₁-C₆alkoxy, —C(O)—(C₁-C₆ alkyl), —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₆ alkyl), —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, and —OCF₃.
 13. The method of claim 12, wherein X³is H; and X⁴ is H.
 14. The method according to any of claims 12 or 13,wherein X⁵ is —CF₃; X⁶ is H; X⁷ is H; and X⁸ is H.
 15. The methodaccording to any of claims 12 or 13, wherein X⁵ is —CH₃; X⁶ is H; X⁷ isH; and X⁸ is —CH₃.
 16. The method according to any of claims 12 or 13,wherein X⁵ is H; X⁶ is Cl; X⁷ is Cl; and X⁸ is H.
 17. The method ofclaim 9 wherein the aldehyde is a compound of the formula

wherein X² is selected from the group consisting of —O—, —CH₂—, —S—,—SO—, —SO₂—, —NH—, —C(O)—, —NHSO₂—,

R² is a ring moiety selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, furyl, thienyl and pyrrolyl, the ring moietybeing substituted by a group of the formula —(CH₂)_(n6)—CO₂R⁸ or apharmaceutically acceptable bioisostere, and optionally furthersubstituted by 1 or 2 substituents independently selected from the groupconsisting of halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), and —NO₂; R⁸ is selected from the groupconsisting of H and C₁-C₆ alkyl; n₅ is an integer selected from 0, 1, 2,or 3; and n₆ is an integer selected from 0, 1, or
 2. 18. The method ofclaim 17, wherein the aldehyde is a compound of the formula

wherein R⁸ comprises a C₁-C₆ alkyl group.
 19. The method according toclaim 18, further comprising the step of removing the R⁸ group to form acarboxylic acid.
 20. The method according to any of claims 17-19 whereinR is benzhydryl; and the Lewis acid is BF₃.
 21. The method according toclaim 20, wherein the silicon hydride reducing agent is triethylsilane.22. The method of claim 10, further comprising subsequently adding anorganic acid to the reaction mixture after the reaction has begun,wherein the organic acid is selected from the group consisting oftrifluoroacetic acid, CCl_(X)H_(3-X)CO₂H where X is 0-3,p-toluenesulfonic acid, and benzenesulfonic acid.
 23. The methodaccording to claim 22, wherein the organic acid is added approximately30-60 minutes after the reaction has begun.
 24. The method of claim 22,wherein the organic acid is trifluoroacetic acid.
 25. The method ofclaim 9, wherein the Lewis acid is selected from the group consisting ofa fluoride, chloride, or triflate salt of boron, aluminium, antimony ora rare earth metal, and pentafluorophenylboronic acid.
 26. The method ofclaim 25 wherein the Lewis acid is selected from the group consisting ofBF₃, boron tris(trifluoromethanesulfonate), and pentafluorophenylboronicacid.
 27. The method of claim 9, wherein the reaction takes place at atemperature in the range of from about −30° C. to about +25° C.
 28. Themethod claim 9, wherein the silicon hydride reducing agent istriethylsilane.